Unlesioned Rats Research Articles

Deficits in a lateralized associative learning task in dopamine-depleted rats with functional recovery by dopamine-rich transplants.

Experimental therapies for Parkinson's disease (PD) are commonly validated in unilateral animal models using simple tests of motor asymmetry such as rotation, stepping and cylinder tests. However, the human disorder is considerably more complex than this, and alternative tests that permit a more complete evaluation of the efficacy and mechanism of action of novel treatments are needed. In this study, an operant task that assesses the selection, initiation and execution of lateralized movements was used to investigate the effects of embryonic dopamine cell transplants in the unilateral medial forebrain bundle (MFB) lesion model of PD. Lesioned Lister Hooded rats had a pronounced contralateral selection and initiation deficit, as well as an impairment in execution of movements bilaterally. They also attempted fewer trials and made more procedural errors than unlesioned rats. Transplantation of fetal dopaminergic neurons to the striatum led to a marked improvement in specific parameters and a more modest improvement in others. The graft improved the contralateral selection deficit and the execution of movements bilaterally, but had no effect on the initiation of contralateral movements. Transplanted rats also attempted more trials and made fewer errors. In contrast, the more commonly used stepping and cylinder tests revealed no functional effect of the graft. This data suggests that this operant task may be a powerful tool for validating and elucidating the mechanism of action of experimental brain repair therapies prior to entering the clinic.

Parafascicular electrical stimulation attenuates nucleus basalis magnocellularis lesion-induced active avoidance retention deficit

Previous experiments from our laboratory showed that retention of two-way active avoidance learning is improved by post-training intracranial electrical stimulation (ICS) of the parafascicular nucleus (PF) and impaired by pre-training electrolytic lesions of the nucleus basalis magnocellularis (NBM). The question investigated here was whether post-training PF ICS is able to attenuate the active avoidance retention deficit observed in rats lesioned pre-training in the NBM. To this goal, the following experimental design was used: rats bilaterally lesioned in the NBM and stimulated in the PF, rats lesioned in the NBM, rats stimulated in the PF, control rats implanted in the PF, and sham-operated rats were first trained in a shuttle-box for a single 30-trial session and tested again following two successive retention intervals (24 h and 11 days). The results showed that: (1) NBM lesions impaired the 11-day performance without affecting either the acquisition or the 24-h retention of the avoidance learning; (2) PF ICS treatment in unlesioned rats improved performance in both retention sessions only when the stimulation was applied in the posterior region of the nucleus; and (3) stimulation of the posterior PF compensated the 11-day retention impairment induced by NBM lesions. These results are discussed in relation to the interaction of arousal systems in the modulation of cognitive processes.

Nigrostriatal pathway laterality in unlesioned old female rats

AbstractWe investigated whether there is an imbalance in the nigrostriatal pathway in unlesioned young (8 weeks) and old (20 months) female rats. Rotation behavior and stepping tests were employed to evaluate the functional laterality of this pathway. In the absence of methamphetamine, there was no preference in the rotational direction in young rats but there was temporally consistent rotational preference in old rats. Methamphetamine injection (5 mg/kg, i.p.) uncovered the imbalance of rotational direction in young rats and enhanced in old rats. Old rat showed a temporally consistent rotational direction preference, as measured weekly for three consecutive weeks. Neither the presence nor the absence of methamphetamine affected rotational direction during the three weeks. Furthermore, statistical analyses revealed lateral malfunctions, which had been predicted from the methamphetamine‐induced rotational test, to be consistent with those revealed by the stepping test in old rats. On the other hand, there was no temporal consistency in young rats. These results suggest that old female rats have a persistent functional imbalance of the nigrostriatal pathway.

Regeneration of Dopaminergic Function in 6-Hydroxydopamine-Lesioned Rats by Neuroimmunophilin Ligand Treatment

Nonimmunosuppressant immunophilin ligands have been found previously to stimulate neurite growth in culture and to promote regeneration of peripheral and central nerve fibers in vivo. To further characterize the effectiveness of these ligands, we have investigated the effect of the immunophilin ligand GPI-1046 in 6-hydroxydopamine (6-OHDA)-lesioned rats. In unlesioned rats, tetanic stimulation of the white matter induced long-term potentiation (LTP) of corticostriatal synaptic transmission as indicated by a 40-100% increase in the field potential amplitudes recorded in striatal brain slices. Unilateral microinjection of 6-OHDA into the substantia nigra resulted in a loss of corticostriatal LTP and in significant abnormality of motor behavior as assessed by amphetamine-induced ipsilateral rotations. Daily treatment of 6-OHDA-lesioned rats with GPI-1046 (10 mg/kg, s.c.) for 1 week reduced amphetamine-induced rotations by 75% and greatly restored the striatal tyrosine hydroxylase immunostaining. In addition, GPI-1046 almost completely restored corticostriatal LTP in 6-OHDA-lesioned animals. LTP in normal animals and that restored by GPI-1046 in lesioned animals were both blocked by the NMDA receptor antagonist APV, suggesting mediation by NMDA receptors. Both LTPs were sensitive to dopamine (DA) receptor antagonists. The nonselective DA receptor antagonist chlorpromazine and the selective D1-D5 receptor antagonist SCH23390 reduced the LTP by 90%. These results demonstrate that the immunophilin ligand GPI-1046 can reverse the abnormalities in the substantia nigra-striatal dopaminergic system that are caused by 6-OHDA, thus providing a potential therapeutic agent for Parkinson's disease.

Effects of systemic 3-nitropropionic acid-induced lesions of the dorsal striatum on cannabinoid and µ-opioid receptor binding in the basal ganglia

Systemic administration of 3-nitropropionic acid (3NPA) in experimental animals produces bilateral striatal lesions similar to those seen in Huntington's disease (HD) caudate and putamen. 3H[-CP55,940 binding to cannabinoid receptors in human basal ganglia nuclei has been shown to be highly susceptible to the earliest pathological changes in the HD brain. In this study, to assess further the suitability of 3NPA-induced striatal lesions as a model for HD neuropathology, we examined the effects of striatal lesions induced by the systemic administration of 3NPA on the binding of 3H[-CP55,940 to pre- and postsynaptic cannabinoid receptors in striatum, globus pallidus, entopeduncular nucleus and substantia nigra pars reticulata and also the effect of 3NPA-induced striatal lesions on the binding of 3H[-DAMGO to mu-opioid receptors in striatal striosomes. Systemic administration of 3NPA induced bilateral and symmetrical lesions in dorsolateral striatum. Within the lesion core, 3H[-CP55,940 and 3H[-DAMGO binding density was reduced to background levels. Beyond the immediate borders of the central core of the 3NPA-induced lesion, striatal binding density was not significantly different from that measured in unlesioned rats. 3H[-CP55,940 binding in globus pallidus, entopeduncular nucleus and substantia nigra in 3NPA-lesioned rats was significantly reduced compared to controls, and the individual decreases were similar for each site. However, these reductions were statistically marginal. These data suggest that, while producing striatal lesions which bear some similarity to those seen in HD, the consequences of 3NPA for striatopallidal and striatonigral efferent projections do not reflect the reported neurodegenerative changes seen in the HD brain.

Anatomic basis of sequence-dependent predictability exhibited by nigral dopamine neuron firing patterns.

Interspike intervals (ISIs) of dopamine (DA) neurons recorded in the substantia nigra are predicted partially by their immediate prior history. This study was designed to assess neuroanatomic origins of these sequential relationships. ISI data recorded from three groups of nigral DA neurons were studied: 1) 16 neurons recorded in unlesioned animals, 2) 14 neurons recorded after forebrain hemisection, 3) 12 neurons recorded after partial forebrain hemisection that reproduced nonspecific effects of the surgical lesion while leaving forebrain connections intact. As predicted, DA neurons recorded after full forebrain hemisection yielded statistically significant reductions in sequential predictability relative to control neurons and neurons recorded following partial hemisection. These data support the hypothesis that the sequence-dependent behavior of DA neurons arise in part from interactions with forebrain structures. ISI sequences recorded from unlesioned rats demonstrated maximum predictability when an average of 3.7 prior events were incorporated into the forecasting algorithm, thereby suggesting a physiological process whose "depth" of history-dependence is approximately 600-800 msec. Additional studies examining the functional significance of sequence-dependent ISI structure exhibited by nigral DA neurons are indicated.

Forebrain serotonin depletion facilitates the acquisition and performance of a conditional visual discrimination task in rats

Three experiments examined the effects of depleting forebrain 5-hydroxytryptamine (5-HT) on the acquisition and performance of an operant conditional discrimination in the visual modality. In the first experiment, rats with 5-HT lesions induced by infusing the neurotoxin 5,7-dihydroxytryptamine intracerebroventricularly acquired the conditional visual discrimination more rapidly than the sham-operated controls. Following acquisition, a series of manipulations of the task parameters tested the effects of the lesion on cognitive, sensory and motivational aspects of performance. In experiment two, the performance of rats that had acquired the task to asymptote before receiving lesions was assessed. The performance of this second group of serotonin-lesioned rats was similar to that of the pre-acquisition lesioned group following all but one manipulation of the task parameters. When the rate of stimulus presentations was increased, rats with forebrain 5-HT depletions were protected from the disruptive effects on performance seen in the sham-operated controls. This latter finding was also observed in a third experiment, in which the infusion of the 5-HT1A receptor partial agonist, 8-hydroxy-2-(di- n-propylamino)tetralin (8-OHDPAT), directly into the dorsal raphé nucleus improved the performance of unlesioned rats following an increase in the rate of stimulus presentations. The results are discussed in terms of the behavioural, neurochemical and neuroanatomical specificity of serotonin function in appetitive learning and the implications for general theories of the function of serotoninergic processes in cognition.

Effects of amygdaloid lesions, hippocampal lesions, and buspirone on black-white exploration and food carrying in rats

Unlesioned rats exploring a black-white two compartment box spent most of the time in the covered, black half of the box and only little time in the uncovered, white half (67 s/5 min). Large radio-frequency lesions of the amygdala or hippocampus did not alter this pattern of exploration, but rats with hippocampus lesions were more active than the other two groups of rats. Treatment with the 5-HT 1A receptor agonist buspirone (0.1 mg/kg, s.c.) increased the time that unlesioned rats spent in the uncovered compartment (103 s), an effect that was less pronounced in hippocampus-lesioned rats and completely abolished by amygdala lesions. In a food transport test, unlesioned rats that traveled from a home cage to an exposed food source consumed small and medium-sized pellets immediately at the food source. Larger pellets, however, were carried back to the home cage for consumption. Rats with amygdala lesions ate fewer pellets at the food source and tended to carry more pellets back to the home cage for consumption than unlesioned rats. Rats with hippocampus lesions carried fewer pellets back to the home cage and ate more pellets at the food source. Buspirone (0.5–1.5 mg/kg, s.c.) reduced the carrying of large food items to the home cage and increased consumption of these pellets at the food source in all groups of rats. These results suggest that neither the amygdala nor the hippocampus play an important role in controlling exploratory behavior in a black-white compartment box, but that the amygdala may have some role in mediating the effect of buspirone to increase exploration of the white/open compartment. Further, the amygdala and hippocampus have opposing influences on the transport of food items to a shelter, the amygdala suppressing food carrying, and the hippocampus enhancing it. Neither structure is essential for the effect of buspirone to reduce food carrying. The hypothesis that limbic structures mediate `fear/anxiety' responses is discussed critically.

Cross-sensitization between footshock stress and apomorphine on self-injurious behavior and neostriatal catecholamines in a rat model of Lesch–Nyhan syndrome

The effects of footshock sensitization (priming), apomorphine (APO) priming and their combination on behavior and neostriatal and cortical catecholamines were examined in adult rats which had neonatally received bilateral intracerebroventricular injections with 6-hydroxydopamine (6-OHDA; a model of Lesch–Nyhan syndrome (LNS)) or vehicle (unlesioned rats). Lesioned (6-OHDA-treated) rats displayed self-biting (SB; 7/20 rats) and self-injurious behavior (SIB; 1/20 rats) during APO priming, but not during footshock priming. During subsequent acute cumulative APO dosing, 20–30% of lesioned rats primed with APO alone or footshock alone displayed SB and SIB. However, SB and SIB incidence in APO+footshock-primed lesioned rats was nearly tripled. Dopamine (DA) synthesis, metabolism and extracellular concentrations (disposition) in unlesioned rats and in cortices of lesioned animals were unaffected by priming. In lesioned rats primed with APO alone or footshock alone, only neostriatal 3-methoxytyramine (3-MT) was significantly increased. However, neostriatal DA and metabolite concentrations (and norepinephrine (NE)) were all significantly elevated in lesioned rats primed with both APO and footshock. These results confirm that neonatal 6-OHDA-induced neostriatal catecholamine depletion can be antagonized by experiential change, suggest that behavioral and neurochemical cross-sensitization between APO and footshock in such rats is unidirectional and support the view that stress can exacerbate the incidence of SIB in LNS.

Lesion-induced axon sprouting in the deafferented striatum of adult rat

Synaptic replacement in rat striatum following a unilateral cortical lesion was investigated using electron microscopy and the anterograde tracer, biotinylated dextrin amine (BDA). In the deafferented striatum evidence of axon sprouting and synapse replacement was seen at 20 days after the lesion and most newly-formed axon terminals were labeled with BDA injected previously into the contralateral cortex. In addition, BDA-labeled fibers from the contralateral cortex formed multiple asymmetric axospinous synapses with deafferented striatal neurons, a morphological feature rarely seen in unlesioned rats. These data suggest that in response to a unilateral cortex lesion axons from the contralateral cortex sprout and reinnervated the deafferented striatal neurons and that reinnervation by `like' afferents maybe crucial for the establishment of functional recovery after the unilateral cortex lesion.

Contributions of the hippocampus, amygdala, and dorsal striatum to the response elicited by reward reduction.

Rats were trained to run down a runway for either 1 or 10 food pellets. After training, those receiving 10 pellets were shifted to 1 pellet. Such shifts typically elicit a temporary decrease in running speed. Groups of normal rats and rats with bilateral lesions of the fimbria-fornix, lateral-basolateral complex of the amygdala, or dorsal striatum were tested with the shifted and unshifted procedures. Separate experiments, identical except for the intertrial intervals (ITIs; 3 min vs. 30 s), were carried out. The data are consistent with the view that an integrated action of multiple neural systems is required to observe the typical response to reward reduction in unlesioned rats. One system that includes the dorsal striatum promotes a reinforced approach response to the goal box. A neural system that includes fimbria-fornix is required to retain information about reduced reward over the 3-min ITI. A system that includes the amygdala may acquire a conditioned aversive response to the goal box after the shift is detected, leading to reduced speeds over testing.

A Simple Design for a Small Fixed Four-Electrode Brain Stimulation Array

Richterich, L. and J. R. Stellar. A simple design for a small fixed four-electrode brain stimulation array. Physiol Behav 62(2) 427–429, 1977.—Anatomical studies of intracranial self-stimulation (ICSS) reward in rats often use the lesion method and, therefore, require repeated behavioral testing before and after the lesion. Other anatomical studies on unlesioned rats use a moveable electrode to permit testing at a number of ICSS sites. Combining these methods would yield still more information, but repeated testing is not possible due to the damage created by lowering the electrode. To meet this need, an array of 4 fixed vertically-spaced electrodes was devised. Electrodes are constructed from strands of 0.14-mm (0.0045″) Teflon-insulated stainless-steel wire, 4 of which are glued into an implantable bundle. A 4-channel IC rotary switch is implanted on the rat's head to permit the use of an inexpensive 2-channel electrode lead and commutator. In our laboratory, electrodes were vertically spaced at 0.3 mm, spanning the dorsoventral extent of the lateral hypothalamus and yielded stable rate-frequency curves over the usual 3–4 month period of behavioral testing.

Expression of fibroblast growth factor‐2 in hypoglossal motoneurons is stimulated by peripheral nerve injury

We have studied the expression of basic fibroblast growth factor 2 (FGF-2) and FGF receptor 1 (FGFR1) in the hypoglossal motor system during degeneration and regeneration by using an RNase protection assay, in situ hybridization, and Western blot analysis. The FGF-2 transcript was found to be weakly expressed in the hypoglossal motoneurons of the adult rat. Both peripheral transection and crush injury of the hypoglossal nerve resulted in a marked up-regulation of the FGF-2 mRNA in motoneurons of the hypoglossal nucleus (with a peak at 10 and 11 days postlesion) as well as in the proximal and distal nerve stumps. The FGFR1 transcript was strongly expressed by hypoglossal motoneurons of unlesioned rats. Neither axotomy nor crush lesion of the hypoglossal nerve revealed any alteration of the expression level and cellular localization in the hypoglossal nucleus, but they did result in a significant increase of the FGFR1 mRNA level in the proximal and distal nerve stump. Western blot analysis of the hypoglossal nucleus revealed the presence of the 21 kD and 23 kD isoforms and of a weak expression of the 18 kD isoform. Hypoglossal nerve transection resulted in a complete down-regulation of the FGF-2 protein 3 days after lesion. After 14 days, however, the level of the three isoforms was increased above the control level. The regulation of FGF-2 in hypoglossal motoneurons after experimental nerve injury is in agreement with the idea of a lesion-related function of FGF-2. Together with previously reported neurotrophic effects, these results suggest that FGF-2 provides trophic support for lesioned motoneurons. At the injury site, FGF-2 could be involved in the regulation of the myelination.

Glial cell line-derived neurotrophic factor: distribution and pharmacology in the rat following a bolus intraventricular injection

Glial cell line-derived neurotrophic factor (GDNF) has been shown to increase dopaminergic parameters in vitro and in vivo and can reduce parkinsonian behaviors in animal models of the disease. This study determined the potential of the lateral ventricle as an administration route for GDNF by examining the distribution and neurochemical consequences of a single intraventricular injection. Autoradiographic analysis showed that intraventricularly administered [ 125I]GDNF was distributed throughout the ventricular system at 1 and 24 h following injection. The cerebral cortex, septum, diagonal band, fimbria, striatum, hippocampus, hypothalamus, substantia nigra/ventral tegmental area, and cerebellum were also labeled. At 7 days, there was still labeling throughout the ventricular system, hypothalamus, substantia nigra, and cerebellum. Twenty-four hours following an intrastriatal injection of [ 125I]GDNF, label was observed in the substantia nigra/ventral tegmental area, demonstrating retrograde transport. The neurochemical effects of intraventricularly administered GDNF (0.1–100 μg) at 7 days post injection were also examined. GDNF significantly increased striatal (approximately 28%) and nigral (up to 40%) dopamine, as well as regulated the dopamine metabolites homovanillic acid and dihydroxyphenylacetic acid. Dopamine levels were unchanged in the frontal cortex. Dopamine content was significantly increased in the hypothalamus (up to 35%), an increase which may contribute to the inhibition of weight gain seen after administration of GDNF. Additionally, dopamine turnover was decreased or unchanged across the brain regions analyzed, which may indicate that in unlesioned rats, intraventricularly administered GDNF stimulates the synthesis and storage of dopamine. This study shows that intraventricularly injected GDNF can access basal ganglia structures, most notably the midbrain dopamine cell body region, and remains present in this area for at least 7 days following a single administration. GDNF differentially increases dopaminergic tone within a variety of brain structures, including the nigrostriatal pathway. These data support the potential effectiveness of intraventricular administered GDNF as a treatment for Parkinson's disease.

Ibotenic acid lesions of the amygdala basolateral complex or central nucleus differentially effect the response to reductions in reward

The present study examined the role of the amygdala in the acquisition and expression of the Crespi effect (Crespi, L.P., Quantitative variation in incentive and performance in the white rat, Am. J. Psychol., 55 (1942) 467–517), also known as successive negative behavioral contrast. In Experiment One rats with bilateral amygdala cannulae were trained to run a straight alley for either a large (ten pellet) or small (one pellet) food reward. After 8 days of training, half of the rats in each reward condition received vehicle or ibotenic acid administered bilaterally into the amygdala. After 4 days of recovery from the induction of the lesions, training resumed. On Day 12 of training, the reward for rats in the large reward condition was shifted to one pellet and this reward level was maintained for the next 4 days of training. Both the lesioned and unlesioned shifted rats exhibited increased latencies to the reduction. However, shifted lesioned rats displayed a more persistent increase in latencies than shifted unlesioned rats, exhibiting significantly longer latencies than those of unlesioned rats by Day 15. This finding suggests that large amygdala lesions may impair learning of the appetitive value of the small reward. Experiment Two examined the effects of discrete ibotenic acid lesions of either the central nucleus or basolateral/lateral complex of the amygdala. Lesions of the central nucleus produced results similar to those of Experiment One. However, in Experiment Two the performance of shifted unlesioned and lesioned groups diverged significantly 1 day earlier, on Day 14. In contrast, lesions of the basolateral/lateral complex reduced the duration of the contrast effect. Shifted lesioned rats exhibited significantly lower latencies than shifted unlesioned rats by the first postshift day, Day 13. This finding suggests that the basolateral/lateral complex may be involved in learning about, or expressing the response to, the aversiveness of reward reduction.

Individual differences in dopamine release but not rotational behavior correlate with extracellular amphetamine levels in caudate putamen in unlesioned rats

Individual differences in dopamine release but not rotational behavior correlate with extracellular amphetamine levels in caudate putamen in unlesioned rats

Individual differences in dopamine release but not rotational behavior correlate with extracellular amphetamine levels in caudate putamen in unlesioned rats

It has been postulated that differences in pharmacokinetics do not contribute to the well-known individual variability in response to amphetamine (AMPH), but this is yet to be investigated thoroughly. Therefore, rotational behavior of outbred rats (Sprague-Dawley, 4 months old) was recorded during microdialysis sessions and striatal microdialysate was analyzed concomitantly for AMPH and dopamine concentrations after a single injection of 2.5 mg/kg AMPH SC. Three hours later these rats received three doses of 5 mg/kg AMPH SC (spaced 2 h apart) and their brain temperature was recorded every 20 min. The most important findings were: 1) the increase in extracellular dopamine was highly correlated with the corresponding peak AMPH levels in the microdialysate; 2) the peak dopamine level in response to 2.5 mg/kg AMPH was predictive of the hyperthermic response observed during 3 x 5 mg/kg AMPH and 3) high versus low rotators differed neither in their AMPH nor in their dopamine extracellular striatal concentrations.

DA1 and DA2 receptor regulation in the striatum of young and old rats after peripheral vestibular lesion

Anatomical, lesion and functional studies have indicated that the mesostriatal dopaminergic (DAergic) system may serve as supravestibular center in posture and locomotion control. Nevertheless, no data are available on the involvement of DAergic systems during vestibular compensation. This study was designed for the analysis of DA1 and DA2 receptors in the striatum by means of quantitative receptor autoradiography 28 days after unilateral or bilateral lesion of the labyrinth in 3-month-old rats. Considering the severe decline of DA content and receptors in striatum and the difference in behavioral recovery after vestibular lesions in old age, we also analyzed 24-month-old, lesioned and unlesioned rats. In young rats, hemilabyrinthectomy caused a bilateral increase (20–30%) of DA1 receptors and a two-fold increase of DA2 receptors. In old rats, we observed a similar modification of DA2 receptors, and a 50% increase in DA1 receptors. Bilabyrinthectomy did not modify DA1 receptor density and decreased DA2 receptor density in young animals, whereas it produced an increase in both DA1 and DA2 in old rats. This study provides evidence for the involvement of the DAergic system during vestibular compensation. Our results also indicate great biochemical plasticity of the remaining DA receptors in the striatum of old rats.

Anatomical and functional evidence for lesion-specific sprouting of corticostriatal input in the adult rat.

Previous studies in our laboratory have shown that cortical lesions induced by thermocoagulation of pial blood vessels, but not by acute aspiration, result in 1) the preservation of control levels of the growth-associated protein (GAP)-43 and 2) a prolonged increase in neurotransmitter gene expression in the denervated dorsolateral striatum. We have examined whether corticostriatal projections from the spared homotypic contralateral cortex contribute to these effects. Adult rats received either a thermocoagulatory or aspiration lesion of the cerebral cortex and, after 30 days, received an injection of the anterograde tracer, Fluoro-Ruby, in the contralateral homotypic cortex. Rats were killed 7 days later, and labeled fibers were examined with fluorescence microscopy in the ipsilateral and contralateral striata. Ipsilateral corticostriatal projections were detected in lesioned and unlesioned rats. Numerous labeled fibers were detected in the contralateral striatum of thermocoagulatory-lesioned but not aspiration-lesioned or control animals, suggesting that contralateral cortical neurons may undergo axonal sprouting in the denervated striatum following a thermocoagulatory lesion of the cortex. To determine whether contralateral corticostriatal fibers play a role in the changes in striatal gene expression induced by the thermocoagulatory lesions, the effects of aspiration lesions, as well as unilateral and bilateral thermocoagulatory lesions of the cortex were compared. Confirming previous results, striatal enkephalin mRNA levels were increased after a unilateral thermocoagulatory lesion. However, they were unchanged after aspiration or bilateral thermocoagulatory lesions, suggesting that sprouting or overactivity of contralateral corticostriatal input contributes to the increase seen after unilateral thermocoagulatory lesions.

Dendritic Remodeling of Dentate Granule Cells Following a Combined Entorhinal Cortex/Fimbria Fornix Lesion

This study examined the time course of dendritic reorganization of dentate granule neurons of the hippocampus following the loss of input from both the fimbria fornix (FF) and the entorhinal cortex (EC). We used the Golgi–Cox stain to assess the morphology of dentate granule neurons at six postlesion time points (4, 8, 14, 30, 45, and 60 days) and dendritic measures included total dendritic length, number of segments, number of branch points, and spine density. We found that as early as 4 days postlesion, total dendritic length and number of segments were significantly decreased with the greatest change occurring in the distal parts of the dendritic arbor located in the outer molecular layer of the dentate gyrus. Dendritic measures related to segment number and dendritic length returned to 70% of intact values by 30 days postlesion and were not significantly different from unlesioned rats at 45 and 60 days postlesion. In contrast, the recovery of spine density was transient. Spine density in the outer molecular layer of the dentate gyrus decreased by 60% at 4 days postlesion and returned to 87% of intact values by 30 days postlesion. However, there was a second loss of dendritic spines along the distal portion of the dendrite between 30 and 60 days postlesion. These data provide evidence that the ability of granule neurons to recover a dendritic morphology similar to that of unlesioned rats is impaired following the combined EC/FF lesion and that the “secondary loss” of dendritic spine density on granule neurons may significantly limit the chances of the hippocampus reforming a synaptic circuitry that could lead to functional recovery after the EC/FF lesion.